Thermodynamic connectivity reveals functional specialization and multiplex organization of extrasynaptic signaling

Abstract

Neural communication operates on both fast synaptic transmission and slower, diffusive extrasynaptic signaling, yet how these two modes jointly organize brain function remains unclear. Here, using the complete synaptic and neuropeptidergic connectomes of \emph{Caenorhabditis elegans}, we develop a unified multiplex framework linking anatomical wiring to functional communication. We infer structure-derived functional connectivity from the synaptic connectome using equilibrium principles from statistical physics, yielding a probabilistic map of information flow across all synaptic pathways, and compare this functional layer directly with the extrasynaptic connectome. This reveals a principled functional specialization across four communication regimes: (i) a topology-dependent layer that reinforces and stabilizes synaptic motor circuits, (ii) a topology-resilient modulatory layer supporting global regulation and behavioral state control, (iii) a purely extrasynaptic network sustaining survival and homeostasis, and (iv) a purely synaptic regime mediating rapid, low-latency sensorimotor processing. Together, these findings reveal that synaptic and extrasynaptic signaling form complementary architectures optimized for speed, modulation, robustness, and survival, and provide a general strategy for integrating structural and modulatory connectomes to understand how distinct communication modes cooperate to sustain coherent brain function.

Figures (12)

• Figure 1: Functional specialization across multiplex communication regimes. The multiplex network partitions into distinct communication regimes with complementary functional roles. The topology-dependent regime reinforces synaptic circuits, particularly in motor control. The topology-resilient regime supports global modulation and behavioral state regulation. The purely extrasynaptic regime sustains survival and homeostatic functions. In contrast, rapid sensorimotor processing is mediated primarily by purely synaptic pathways. Together, these regimes define a principled functional organization across signaling modes specialized for speed, modulation, robustness, and survival.
• Figure 2: Scale-dependent propagation of neural emittance. KMS-derived emittance profiles illustrate how information flow from a source neuron reorganizes across inverse temperature regimes ($\beta$). At high inverse temperature ($\beta \uparrow$), communication is localized and dominated by direct synaptic connections. As $\beta$ decreases, multi-step pathways increasingly contribute, producing distributed connectivity patterns. Near the critical regime ($\beta \approx \beta_c$), information flow becomes maximally dispersed across the network. Node size reflects distance from the source, and edge coloring distinguishes active from inactive communication pathways. This scale dependence underlies the construction of the structure-informed functional connectome.
• Figure 3: Functional multiplex framework integrating synaptic and extrasynaptic communication. Schematic of the two-layer network combining the structure-informed functional connectome (SIFC), derived from synaptic wiring using the KMS framework, with the extrasynaptic neuropeptidergic connectome. Directed edges represent probabilistic information flow that may arise from direct or multi-step interactions. Nodes are colored by neuronal class (sensory: yellow, interneuron: green, motor: pink). This multiplex representation provides a common functional reference for comparing fast synaptic and diffusive extrasynaptic communication.
• Figure 4: Topology-dependent extrasynaptic regime reinforcing synaptic circuits. Network representation of extrasynaptic connections that overlap with significant structure-informed functional connectivity. Node size reflects degree within this regime, with labels shown for the most connected neurons. This subnetwork is enriched for locomotion-related motor neurons and closely mirrors synaptic communication structure, showing that these extrasynaptic pathways are constrained by and reinforce underlying synaptic topology.
• Figure 5: Topology-resilient extrasynaptic regime supporting global modulation. Extrasynaptic connections that persist independently of synaptic topology, remaining stable under degree-preserving randomization. Node size indicates connectivity within the regime. This network is dominated by interneurons involved in behavioral state regulation and global coordination, consistent with a distributed modulatory layer that operates independently of precise anatomical wiring.